Atezolizumab Plus CArboplatin Plus Nab-paclitaxel

Inclusion Criteria:

1. Signed Informed Consent Form
2. Women or men aged ≥18 years
3. Histologically or cytologically confirmed adenocarcinoma of the breast with metastaticdisease
4. Hormone receptor-negative (ER and PgR < 10%) and HER2-negative (IHC 0,1+ or 2+ ISH notamplified) breast cancer, based on the status of the primary tumor and/or the biopsyof metastatic disease before starting first-line therapy and assessed by locallaboratory.
5. Patients ER and PgR < 1% eligible to receive atezolizumab in combination withnab-paclitaxel as standard of care treatment for metastatic triple-negative breastcancer (TNBC), regardless of study participation.
6. PD-L1 positive defined as expression on tumor-infiltrating immune cells ≥1% (SP142PD-L1 immunohistochemical assay, Ventana Medical Systems), based on the status of theprimary tumor and/or the biopsy of metastatic disease before starting first-linetherapy and assessed by local laboratory
7. Availability of a representative tumor specimen for translational research
8. Eligible for first-line taxane and carboplatin chemotherapy
9. No prior chemotherapy or targeted systemic therapy (including endocrine therapy) forinoperable locally advanced or metastatic TNBC. Prior radiation therapy for metastaticdisease is permitted. There is no required minimum washout period for radiationtherapy; however, patients should have recovered from the effects of radiation beforeenrollment
10. Previous chemotherapy with taxanes and/or carboplatin for early breast cancer (neoadjuvant or adjuvant setting) is permitted if completed ≥12 months before studyentry
11. Previous therapy with immune checkpoint inhibitors for early breast cancer (neoadjuvant or adjuvant setting) is permitted if completed ≥12 months before studyentry
12. ECOG performance status of 0 or 1
13. Life expectancy ≥ 12 weeks
14. Measurable or evaluable disease as defined by RECIST v1.1.
15. Adequate hematologic and end-organ function, defined by laboratory results obtainedwithin 2 weeks prior to the first study treatment (Cycle 1, Day 1)
16. Negative human immunodeficiency virus (HIV) test at screening
17. Negative hepatitis B surface antigen (HBsAg) test at screening
18. Negative total hepatitis B core antibody (HBcAb) test at screening, or positive HBcAbtest followed by a negative hepatitis B virus (HBV) DNA test at screening. The HBV DNAtest will be performed only for patients who have a positive HBcAb test
19. Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV antibodytest followed by a negative HCV RNA test at screening. The HCV RNA test will beperformed only for patients who have a positive HCV antibody test
20. Women of child bearing potential must agree to either use a contraceptive method witha failure rate of ≤ 1% per year or to remain abstinent (refrain from heterosexualintercourse) during the treatment period and for at least 5 months after the last doseof atezolizumab, or for at least 6 months after the last dose of paclitaxel. A womanis considered to be of childbearing potential if she is postmenarcheal, has notreached a postmenopausal state (≥ 12 continuous months of amenorrhea with noidentified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus). Examples of contraceptive methods with a failurerate of ≤ 1% per year include bilateral tubal ligation, male sterilization, hormonalcontraceptives that inhibit ovulation, hormone-releasing intrauterine devices, andcopper intrauterine devices. The reliability of sexual abstinence should be evaluatedin relation to the duration of the clinical trial and the preferred and usuallifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation,symptothermal, or post-ovulation methods) and withdrawal are not acceptable methods ofcontraception
21. Women of child bearing potential must have a negative serum pregnancy test resultwithin 7 days prior to initiation of study drug
22. For men: agreement to remain abstinent (refrain from heterosexual intercourse) or usecontraceptive measures and agreement to refrain from donating sperm

Exclusion Criteria:

1. Spinal cord compression not definitively treated with surgery and/or radiation, orpreviously diagnosed and treated spinal cord compression without evidence that diseasehas been clinically stable for at least 2 weeks prior to enrollment.
2. Known central nervous system (CNS) disease, except for treated asymptomatic CNSmetastases, provided all of the following criteria are met:
3. No ongoing requirement for corticosteroids as therapy for CNS disease (anticonvulsants at a stable dose are allowed)
4. No stereotactic radiation within 7 days or whole-brain radiation within 14 daysprior to enrollment
5. No evidence of progression or hemorrhage after completion of CNS directed therapyNote: Patients with new asymptomatic CNS metastases detected at the screeningscan must receive radiation therapy and/or surgery for CNS metastases. Followingtreatment, these patients may then be eligible, if all other criteria above aremet.
6. Uncontrolled pleural effusion, pericardial effusion, or ascites (Note: patients withindwelling catheters, such as PleurX® are allowed)
7. Uncontrolled tumor-related pain
8. Patients requiring narcotic pain medication must be on a stable regimen at studyentry.
9. Symptomatic lesions (e.g., bone metastases or metastases causing nerveimpingement) amenable to palliative radiotherapy should be treated prior toenrollment. Patients should be recovered from the effects of radiation. There isno required minimum recovery period.
10. Asymptomatic metastatic lesions whose further growth would likely causefunctional deficits or intractable pain (e.g., epidural metastasis that is notpresently associated with spinal cord compression) should be considered forloco-regional therapy if appropriate prior to enrollment.
11. Uncontrolled hypercalcemia (>1.5 mmol/L [>6 mg/dL] ionized calcium or serum calcium [uncorrected for albumin] >3 mmol/L [>12 mg/dL] or corrected serum calcium >ULN) orclinically significant (symptomatic) hypercalcemia a) Patients who are receiving bisphosphonate therapy or denosumab specifically toprevent skeletal events and who do not have a history of clinically significant (symptomatic) hypercalcemia are eligible.
12. Malignancies other than TNBC within 5 years prior to enrollment, with the exception ofthose with a negligible risk of metastasis or death and treated with expected curativeoutcome (such as adequately treated carcinoma in situ of the cervix, non-melanoma skincarcinoma, or Stage I uterine cancer)
13. Pregnant or lactating women, or intending to become pregnant during the study
14. Evidence of significant uncontrolled concomitant disease that could affect compliancewith the protocol or interpretation of results, including significant liver disease (such as cirrhosis, uncontrolled major seizure disorder, or superior vena cavasyndrome)
15. Significant cardiovascular disease, such as New York Heart Association (NYHA) cardiacdisease (Class II or greater), myocardial infarction within 3 months prior to firstdose, unstable arrhythmias, or unstable angina
16. Patients with a known left ventricular ejection fraction (LVEF) < 40% will beexcluded
17. Patients with known coronary artery disease, congestive heart failure not meetingthe above criteria, or LVEF < 50% must be on a stable medical regimen that isoptimized in the opinion of the treating physician, in consultation with acardiologist if appropriate
18. Presence of an abnormal electrocardiogram (ECG) that is clinically significant in theinvestigator's opinion, including complete left bundle branch block, second- or thirddegree heart block, evidence of prior myocardial infarction, or QT interval correctedusing Fridericia's formula (QTcF) >470 ms demonstrated by at least two consecutiveECGs
19. Serious infection requiring antibiotics within 2 weeks prior to enrollment, includingbut not limited to infections requiring hospitalisation or IV antibiotics, such asbacteremia, or severe pneumonia
20. Major surgical procedure within 4 weeks prior to enrollment or anticipation of theneed for a major surgical procedure during the study other than for diagnosis Note:Placement of central venous access catheter(s) (e.g., port or similar) is notconsidered a major surgical procedure and is therefore permitted
21. Treatment with investigational therapy within 30 days prior to initiation of studytreatment
22. History of severe allergic, anaphylactic, or other hypersensitivity reactions tochimeric or humanized antibodies or fusion proteins
23. Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamsterovary (CHO) cells or any component of the atezolizumab formulation
24. History of autoimmune disease, including but not limited to myasthenia gravis,myositis, autoimmune hepatitis, systemic lupus erythematosus (SLE), rheumatoidarthritis (RA), inflammatory bowel disease, vascular thrombosis associated withantiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome,Guillain-Barré syndrome, multiple sclerosis (MS), vasculitis, or glomerulonephritis (Note: Patients with a history of autoimmune-related hypothyroidism on a stable doseof thyroid replacement hormone and patients with controlled Type 1 diabetes mellituson a stable insulin regimen may be eligible for this study)
25. Prior allogeneic stem cell or solid organ transplantation
26. History of idiopathic pulmonary fibrosis (IPF, including pneumonitis), drug-inducedpneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenicorganizing pneumonia), or evidence of active pneumonitis on screening chest CT scan. (Note: History of radiation pneumonitis in the radiation field [fibrosis] ispermitted)
27. Positive test for human immunodeficiency virus (HIV)
28. Active hepatitis B (positive hepatitis B surface antigen [HBsAg] test or hepatitis Bvirus [HBV] DNA polymerase chain reaction [PCR] test at screening) or hepatitis C (positive hepatitis C virus antibody test at screening). Note:

• Patients with past HBV infection or resolved HBV infection (defined as havingnegative HBsAg and HBV DNA test but a positive hepatitis B core antibody [HBcAb]test) are eligible
• Patients positive for hepatitis C virus (HCV) antibody are eligible only if PCRis negative for HCV ribonucleic acid (RNA)

21. Current treatment with anti-viral therapy for HBV
22. Active tuberculosis
23. Receipt of a live, attenuated vaccine within 4 weeks prior to enrollment oranticipation that such a live, attenuated vaccine will be required during the studyNote: Patients must agree not to receive live, attenuated influenza vaccine (e.g.,FluMist®) within 28 days prior to enrollment, during treatment or within 5 monthsfollowing the last dose of atezolizumab
24. Treatment with systemic immunostimulatory agents (including but not limited tointerferons or interleukin [IL]-2) within 4 weeks or five half-lives of the drug (whichever is longer) prior to enrollment
25. Treatment with systemic immunosuppressive medications (including but not limited tocorticosteroids, cyclophosphamide, azathioprine, cyclosporine, methotrexate,thalidomide, and antitumour necrosis factor [TNF] agents) within 2 weeks prior toenrollment, or anticipated requirement for systemic immunosuppressive medicationsduring the trial
26. Patients who have received acute, low-dose (≤ 10 mg oral prednisone orequivalent), systemic immunosuppressant medications may be enrolled in the study
27. Patients with a history of allergic reaction to IV contrast requiring steroidpretreatment should have baseline and subsequent tumor assessments performedusing MRI
28. The use of corticosteroids (≤ 10 mg oral prednisone or equivalent) for chronicobstructive pulmonary disease, mineralocorticoids (e.g., fludrocortisone) forpatients with orthostatic hypotension, and low dose supplemental corticosteroidsfor adrenocortical insufficiency are allowed
29. Poor peripheral venous access
30. Illicit drug or alcohol abuse within 12 months prior to screening, in theinvestigator's judgment
31. Any other serious medical condition or abnormality in clinical laboratory tests that,in the investigator's judgment, precludes the patient's safe participation in andcompletion of the study
32. History of hypersensitivity reactions to paclitaxel or other drugs formulated in thesame solvent as nab-paclitaxel
33. History of hypersensitivity reactions to carboplatin