A Study to Assess Overall Response Rate by Inducing an Inflammatory Phenotype in Metastatic BReast cAnCEr With the Oncolytic Reovirus PeLareorEp in CombinaTion With Anti-PD-L1 Avelumab and Paclitaxel - BRACELET-1 Study

Inclusion Criteria:

1. Female patients ≥ 18 years of age at the time of signing the informed consent form (ICF).
2. Must have a histological/cytological diagnosis of breast cancer. Disease must be:

   * Positive for estrogen receptor (ER) and/or progesterone receptor (PgR) as defined by

     ≥ 1% tumor cell nuclei immunoreactive.
   * Negative for HER2 amplification / overexpression as defined per the American Society of Clinical Oncology - College of American Pathologists (ASCO-CAP) guidelines. However, patients with HER2 equivocal disease for whom HER2 targeted therapy isn't indicated are also eligible for enrollment.
3. ECOG performance status of 0-1
4. Must have unresectable locally advanced or metastatic disease, for which no curative therapy exists and for which systemic chemotherapy is indicated.
5. Measurable disease as defined by RECIST Version 1.1
6. Prior Hormonal Therapy:

   * Patients must have progressed on at least 1 hormone-based therapy with a CDK4/6 inhibitor. Patients who received a CDK4/6 inhibitor in the adjuvant setting and progressed while on or within 6 months of discontinuation of CDK4/6 inhibitor therapy are eligible.
   * Prior mTOR inhibitor therapy is allowed but is not required.
7. Ability to understand and willingness to sign IRB-approved informed consent.
8. Willing to provide blood samples for research
9. Adequate organ function as measured by the following criteria, obtained ≤ 2 weeks prior to registration:

   Hematology:
   * Neutrophils ≥ 1.5 x 10\^9/L
   * Platelets ≥ 100 x 10\^9/L
   * Lymphocytes ≥ 0.8 x 10\^9/L
   * INR \< 1.5x ULN (Unless on therapeutic anticoagulation)
   * PTT \< 1.5x ULN

   Biochemistry:
   * Serum Creatinine ≤ 1.5x ULN
   * Total Bilirubin ≤ 1.0x ULN (unless due to Gilbert's Disease and direct bilirubin \<ULN)
   * ALT and AST ≤ 3x ULN (Note: ≤ 5x ULN if documented liver metastasis)
   * Proteinuria ≤ Grade 2\* (using spot testing; if Grade 3 repeat with mid-stream urine; if still Grade 3 then urine collection for 24 hours to confirm Grade 0, 1 or 2) \*as per National Cancer Institute Common Terminology Criteria for Adverse (NCI-CTCAE)
10. Women must not be pregnant or breastfeeding since we do not know the effects of the study drugs on the fetus or breastfeeding child. All sexually active females of childbearing potential (not surgically sterilized and between menarche and 1 year post menopause) must have a blood test to rule out pregnancy within 2 weeks prior to registration.
11. Sexually active women of child-bearing potential with a non-sterilized male partner must agree to use 2 methods of adequate contraception (hormonal plus barrier or 2 barrier forms) OR abstinence prior to study entry, for the duration of study participation, and for 3 months following last dose of study drugs. Method of contraception must be documented. NOTE: If a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately.

Exclusion Criteria:

1. No major surgery within 21 days prior to beginning study treatment. Major surgery \>21 days prior to beginning study treatment is permitted provided that the patient has recovered adequately to receive systemic chemotherapy. NOTE: Placement of a vascular access device is not considered major surgery.
2. Patients who have received radiation treatment within 14 days of beginning study treatment are excluded. Patients who have received palliative radiation ≥ 14 days prior to beginning study treatment may enroll if they have recovered from all local and systemic side effects to ≤ Grade 1 (NCI-CTCAE).
3. No prior chemotherapy in the advanced/metastatic setting is allowed. Patients may have received chemotherapy in the (neo)adjuvant setting. Patients receiving (neo)adjuvant taxanes must have a disease-free interval of at least 12 months.
4. No known active, uncontrolled or symptomatic Central Nervous System (CNS) metastases, carcinomatous meningitis, or leptomeningeal disease as indicated by clinical symptoms,cerebral edema, and/or progressive growth. Patients with CNS metastases treated with radiation therapy (Whole-Brain Radiation Therapy \[WBXRT\] or Stereotactic Radiotherapy \[SRS\]) are eligible if, \>28 days following completion of XRT, they show stable disease on post-treatment MRI/CT, are off corticosteroids, and are neurologically stable.
5. No known history of other malignancies, except for adequately treated non-melanoma skin cancer or solid tumors curatively treated with no evidence of disease for \>3 years.
6. Not on chronic immunosuppressive therapy including, but not exclusively, steroids (≥ 10 mg prednisone a day or equivalent) or monoclonal antibodies, chronic methotrexate or cyclophosphamide, tacrolimus or sirolimus.
7. No known HIV infection. Testing not required in absence of clinical suspicion.
8. No known active Hepatitis B Virus (HBV) or Hepatitis C Virus (HCV) infection or undergoing anti-viral treatment. Testing for HBV/HCV is not required in absence of clinical suspicion.
9. No concurrent disease or condition that would interfere with study participation or safety,such as any of the following:

   • Active, clinically significant infection either Grade \>2 by CTCAE V5.0 or requiring the use of parenteral anti-microbial agents within 14 days before registration.
10. No active or history of any autoimmune disease (patients with diabetes Type 1, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible) or immunodeficiencies.
11. Patients may not have evidence of uncontrolled cardiovascular conditions, including uncontrolled hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure (New York Heart Association \[NYHA\] Class III or higher), unstable angina, or myocardial infarction within the past 6 months prior to registration. NOTE: Patients with asymptomatic rate-controlled atrial fibrillation may participate.
12. Patients may not have other significant diseases (for example, inflammatory bowel disease), which, in the opinion of the Investigator, might impair the patient's tolerance of trial treatment.
13. Patients with a known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent are not eligible.
14. Patients who have contraindications to treatment with paclitaxel and/or neuropathy \>Grade 2 are not eligible.
15. Patients who have not recovered from clinically significant acute toxicities of previous therapy are not eligible, except treatment-related alopecia or stable sensory neuropathy ≤ Grade 2.
16. No prior therapy with any investigational anti-cancer therapy within 30 days. Prior immunotherapies are prohibited.
17. No prior therapy with checkpoint inhibitors (e.g., anti-PD-1/PD-L1 antibodies), checkpoint agonist agents (e.g., anti-GITR, anti-OX40 antibodies) and/or another active immunotherapy in breast cancer such as cancer vaccines or oncolytic virsus.
18. Patients with any serious medical or psychiatric illness that could, in the Investigator's opinion, potentially interfere with the completion of the treatment according to the protocol, are not eligible.
19. Patients with legal incapacity or limited legal capacity are not eligible.
20. Patients with known alcohol or drug abuse are not eligible.
21. Patients may not participate in any other therapeutic clinical trials, including those with other investigational agents not included in this trial, throughout the duration of this study.
22. Patients may not have any vaccine, including against SARS-COV-2 (COVID-19) \<14 days prior to Cycle 1 Day 1 nor in the first cycle of study treatment. Inactivated vaccines (including against COVID-19 or seasonal influenza) are permitted after the first cycle of study treatment is complete.