Clinical trial NCT04215146: 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
Official title: 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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Breast Cancer Metastatic
Keywords: Breast
Breast Cancer
Breast Cancer Metastatic
Locally Advanced Breast Cancer
Pelareorep
Avelumab
Paclitaxel
Reovirus
Oncolytic virus
HR+ breast cancer
HER2- breast cancer
Breast malignancy
Lead sponsor: Oncolytics Biotech
Sponsor class: INDUSTRY
Collaborators: name: PrECOG, LLC.
First posted: 2020-01-02
Enrollment: 48
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to find out the possible anti-cancer effect of pelareorep in combination with chemotherapy \[paclitaxel\] and avelumab in treating a type of breast cancer called Hormone Receptor positive (HR+)/Human Epidermal Growth Factor Receptor 2 negative(HER2-) breast cancer, which is either locally advanced or has metastasized (cancer that has spread in your body). The study will investigate if pelareorep in combination with paclitaxel and avelumab is more effective than paclitaxel alone, or pelareorep and paclitaxel. The safety of the combination treatments will also be evaluated.

Detailed description: 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 + paclitaxel + avelumab. A three patient safety run-in will be conducted in the cohort for pelareorep + paclitaxel + 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Overall Response Rate
timeFrame: at week 16
Secondary outcomes:
Other outcomes:
measure: The Number of Patients With Adverse Events and Serious Adverse Events
timeFrame: From first day of study treatment to 30 days after of last day of study treatment; up to 27 months
measure: Changes in the Peripheral and Tumor T Cell Clonality.
timeFrame: Up to 2 years of study treatment
measure: Overall Response Rate
timeFrame: Up to 2 years of study participation
measure: Overall Survival
timeFrame: Up to 2 years of study participation
Locations:
city: Miami
country: United States
facility: University of Miami Sylvester Comprehensive Cancer Center
state: Florida
city: Urbana
country: United States
facility: Carle Cancer Center
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University Melvin and Bren Simon Comprehensive Cancer Center
state: Indiana
city: New Orleans
country: United States
facility: Ochsner Clinic Foundation
state: Louisiana
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: New Brunswick
country: United States
facility: Rutgers Cancer Institute of New Jersey
state: New Jersey
city: Bronx
country: United States
facility: Montefiore Medical Park
state: New York
city: Buffalo
country: United States
facility: Roswell Park
state: New York
city: New York
country: United States
facility: Icahn School of Medicine at Mount Sinai
state: New York
city: Rochester
country: United States
facility: University of Rochester Medical Center
state: New York
city: Cleveland
country: United States
facility: University Hospitals Cleveland Medical Center
state: Ohio
city: Columbus
country: United States
facility: Ohio State University Comprehensive Cancer Center
state: Ohio
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Philadelphia
country: United States
facility: Thomas Jefferson University Hospital, Sidney Kimmel Cancer Center
state: Pennsylvania
city: Philadelphia
country: United States
facility: Fox Chase Cancer Center
state: Pennsylvania
city: Charlottesville
country: United States
facility: University of Virginia Cancer Center
state: Virginia
city: Richmond
country: United States
facility: VCU/Massey Cancer Center
state: Virginia
city: Morgantown
country: United States
facility: West Virginia University
state: West Virginia
Study officials:
References: