A Phase III Study of Bevacizumab and Paclitaxel in Combination with Atezolizumab As a Treatment for Locally Advanced Unresectable or Metastatic Hormone Receptor-positive HER2 Negative Breast Cancer

Inclusion Criteria:

1. Histologically diagnosed as breast cancer (invasive cancer).

2. Histologically diagnosed as hormone receptor positive (at least one of ER and PgR ispositive) and HER2 negative. However, if there are multiple specimens, thehistological results of the most recent specimen that meets the eligibility criteria

3. and 2. should be used.

4. Diagnosed with advanced recurrent breast cancer (either unresectable locallyadvanced breast cancer, recurrent breast cancer, or Stage IV breast cancer).

5. Age 20 years or older on the date of registration. Either male or female areacceptable.

6. ECOG performance status (PS) of 0-2.

7. Patients must have measurable lesions.

8. Hormone refractory[*a] or life-threatening metastases [*b].

9. Hormone refractory: Recurrence within 2 years after the start of postoperativeendocrine therapy, or progression within 6 months of endocrine therapy foradvanced recurrent breast cancer.

10. Life-threatening metastases: Symptomatic metastases that require symptomaticrelief through urgent tumor shrinkage. Examples include multiple livermetastases, lung metastases, carcinomatous pleurisy, and carcinomatouslymphangitis.

11. PD-L1 status has been confirmed by a central measurement institute.

12. No active brain metastases that require treatment.

13. No history of prior chemotherapy treatment for advanced or recurrent breast cancer.However, in case that a history of preoperative/postoperative chemotherapy includingpaclitaxel or docetaxel, it is acceptable if at least 6 months have passed since thelast dose.

14. The most recent laboratory test within 14 days prior to enrollment (the same day ofthe week two weeks prior to the date of enrollment is acceptable) must meet all ofthe following

15. Neutrophil count ≥1,500/mm^3

16. Hemoglobin ≥ 9.0 g/dL (No blood transfusion within 14 days prior to the date ofblood collection for the test used for registration)

17. Platelet count ≥10×104/mm^3

18. Total bilirubin ≤ 1.5 mg/dL

19. AST ≤ 100 IU/L (≤ 150 IU/L if liver metastasis is present)

20. ALT ≤ 100 IU/L (≤ 150 IU/L in case of liver metastasis)

21. Serum creatinine ≤1.2 mg/dL

22. PT-INR ≤ 1.5, but PT-INR ≤ 3.0 if the patient is taking anticoagulants such aswarfarin prophylactically.

23. Urine protein (test paper method) of 1+ or less

24. For women of childbearing potential [*a], consent for contraception from the time ofobtaining consent until at least 6 months after completion of the protocoltreatment. For lactating patients, the patient agrees not to breastfeed from thestart of protocol treatment until at least 6 months after the end of protocoltreatment. For men, they agree to use contraception from the start of protocoltreatment until at least 6 months after the end of protocol treatment [*b].

25. Women of childbearing potential: Women who have experienced menarche, have notundergone sterilization (hysterectomy or bilateral oophorectomy), and have notundergone menopause. Menopause is defined as the absence of menstruation formore than 12 months without another medical reason such as drug administration.

26. Examples of contraceptive methods: condoms, pessaries, oral contraceptives, useof intrauterine devices, etc.

27. The patient's written consent to participate in the study has been obtained.

Exclusion Criteria:

1. Active multiple cancer. However, the following are excluded: ①Completely resectedcancers: basal cell carcinoma, Stage I spinous cell carcinoma, intraepithelialcarcinoma, intramucosal carcinoma, superficial bladder cancer, ② gastrointestinaltract cancer that has been curatively resected by ESD or EMR, and ③ other cancersthat have not recurred for more than 5 years.

2. Infectious diseases that require systemic treatment.

3. Complicated active gastrointestinal ulcer.

4. Patients must have poorly controlled hypertension (systolic blood pressure ≥150 mmHgand/or diastolic blood pressure ≥100 mmHg) despite the use of two or moreantihypertensive agents.

5. Patients must have symptomatic congestive heart failure, unstable angina, orarrhythmia requiring treatment at the time of enrollment.

6. History of myocardial infarction within 1 year prior to enrollment.

7. Major surgery or incisional biopsy or significant trauma within 28 days prior toenrollment; placement of a CV port is not considered major surgery.

8. Patients with deep vein thrombosis or pulmonary embolism at the time of enrollment,or a history of such within 1 year prior to enrollment.

9. Use of anticoagulants (except aspirin of 324 mg/day or less) within 10 days prior toenrollment.

10. Patients with a history of idiopathic pulmonary fibrosis, organizing pneumonia (bronchiolitis obliterans, etc.), drug-induced pneumonitis, or idiopathicpneumonitis. However, patients with a history of drug-induced pneumonitis who areasymptomatic at the time of enrollment can be enrolled if they undergo regular chestX-ray examinations and careful follow-up including auscultation and medicalexamination.

11. Findings of active pneumocystitis on chest CT. However, a history of localizedradiation pneumonitis (fibrosis) in the irradiation field is inclusible.

12. Patients have been treated with investigational atezolizumab, or other immunecheckpoint inhibitors (e.g., anti-PD-1, anti-PD-L1, anti-CTLA-4 antibody drugs), orimmunostimulants (e.g., interferon, interleukin-2).

13. Active autoimmune disease, immunodeficiency, or history thereof (e.g., myastheniagravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoidarthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener'sgranulomatosis, Sjogren's syndrome, Guillain-Barré syndrome, multiple sclerosis,etc.). However, the following are inclusible. Patients with autoimmunehypothyroidism who are using a stable dose of thyroid hormone preparations. Patientswith eczema, psoriasis, lichen simplex chronicus, or vitiligo vulgaris whosesymptoms are limited to the skin, and whose rash accounts for less than 10% of thebody surface area and is well controlled by topical application of low potencycorticosteroids alone. No acute exacerbation of the underlying disease requiringsolaren long-wavelength ultraviolet therapy, methotrexate, retinoids, biologics,oral calcineurin inhibitors, high potency or oral corticosteroids within the past 12months.

14. Patients who have received a live attenuated vaccine within 4 weeks prior toenrollment or are expected to require a live attenuated vaccine within 5 months ofcompletion of protocol treatment.

15. Patients have not recovered from clinically significant toxicity caused by previoustherapy, except for alopecia and Grade 1 peripheral neuropathy.

16. Hypersensitivity or contraindication to any component of the therapeutic agent,including macrogol glycerol ricinoleate (Cremophor®), an additive to paclitaxel.

17. Positive for HIV antibodies, HBs antigen, or HCV antibodies (however, if HCVantibodies are positive but HCV-RNA is not detected, it is not excluded).

18. Negative for HBs antigen, positive for HBs antibody or HBc antibody, and positivefor HBV-DNA quantification.

19. Women who are pregnant, lactating, or may be pregnant.

20. Patients with psychosis or psychiatric symptoms that interfere with daily life andare judged to be difficult to participate in the study.