This is an open-label randomized Phase 2, 3-cohort study to evaluate the safety and efficacy
of pelareorep, paclitaxel and avelumab in Hormone Receptor+ (HR+)/Human Epidermal Growth
Factor Receptor 2 negative (HER2-) with endocrine-refractory metastatic breast cancer.
Patients will be randomized to one of three treatment cohorts: paclitaxel alone, pelareorep +
paclitaxel, or pelareorep + paclitazel + avelumab. A three patient safety run-in will be
conducted in the cohort for pelareorep + paclitazel + avelumab prior to beginning
randomization into all three cohorts.
Patients will give mandatory blood samples and optional tumor biopsies, which will be
analyzed for biomarkers to determine the immunological changes within the tumor
microenvironment and peripheral blood in patients treated with paclitaxel alone, in
combination with pelareorep, and in combination with pelareorep and avelumab.
1. Female patients ≥ 18 years of age at the time of signing the informed consent form
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
≥ 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:
- 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
- Serum Creatinine ≤ 1.5x ULN
- Total Bilirubin ≤ 1.0x ULN (unless due to Gilbert's Disease and direct bilirubin
- 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
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
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
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
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
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
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 non-oncology vaccine therapies for prevention of infectious
disease (for example, seasonal flu vaccine, human papilloma virus vaccine) within 4
weeks of study drug administration. Vaccination while on study is also prohibited
except for administration of the inactivated influenza vaccine.