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

• ClinicalTrials.gov Identifier: NCT04215146
• Recruitment Status: Active, not recruiting
• First Posted: January 2, 2020
• Last Update Posted: September 2, 2022
• Sponsor: Oncolytics Biotech
• Collaborator: PrECOG, LLC.
• Information provided by (Responsible Party): Oncolytics Biotech

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Breast Cancer Metastatic	Drug: Paclitaxel; Biological: Pelareorep; Drug: Avelumab	Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 48 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: June 10, 2020
• Actual Primary Completion Date: August 1, 2022
• Estimated Study Completion Date: July 2024

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Cohort 1; Patients receive paclitaxel alone.	Drug: Paclitaxel; Paclitaxel 80 mg/m^2 1-hour IV infusion on days 1, 8, and 15 of a 28-day cycle.
Experimental: Cohort 2; Patients receive pelareorep + paclitaxel.	Drug: Paclitaxel; Paclitaxel 80 mg/m^2 1-hour IV infusion on days 1, 8, and 15 of a 28-day cycle.; Biological: Pelareorep; Pelareorep 4.5 x 10^10 TCID50 1-hour IV infusion days 1, 2, 8, 9, and 15, 16 of a 28-day cycle.
Experimental: Cohort 3; Patients receive pelareorep + paclitaxel + avelumab.	Drug: Paclitaxel; Paclitaxel 80 mg/m^2 1-hour IV infusion on days 1, 8, and 15 of a 28-day cycle.; Biological: Pelareorep; Pelareorep 4.5 x 10^10 TCID50 1-hour IV infusion days 1, 2, 8, 9, and 15, 16 of a 28-day cycle.; Drug: Avelumab; Avelumab 10 mg/kg (not more than 800 mg) 1-hour IV infusion days 3 and 17 of a 28-day cycle.

Outcome Measures

Primary Outcome Measures :

1. Overall response rate [ Time Frame: at week 16. ]
   Overall response rate at week 16 according to RECIST V1.1.
2. To describe the safety and tolerability of the combinations of pelareorep, paclitaxel and avelumab as graded by the NCI CTCAE v. 5.0. [ Time Frame: From start of study treatment to 30 days after of last dose of study treatment. ]
   Type, incidence, severity (as graded by the NCI CTCAE v. 5.0), seriousness and attribution to the study medications of AEs and any laboratory abnormalities.

Other Outcome Measures:

1. Changes in the peripheral and tumor T cell clonality. [ Time Frame: Up to 2 years of study treatment ]
   Assessed by T cell receptor (CDR3 variable chain) sequencing in all patients.
2. Overall response rate [ Time Frame: Up to 2 years of study participation ]
   Overall response rate according to RECIST V1.1
3. Overall Survival [ Time Frame: Up to 2 years of study participation ]
   Overall Survival assessed at end of study

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

United States, Florida

University of Miami Sylvester Comprehensive Cancer Center

Miami, Florida, United States, 33136

United States, Illinois

Carle Cancer Center

Urbana, Illinois, United States, 61801

United States, Indiana

Indiana University Melvin and Bren Simon Comprehensive Cancer Center

Indianapolis, Indiana, United States, 46202

United States, Louisiana

Ochsner Clinic Foundation

New Orleans, Louisiana, United States, 70121

United States, Missouri

Washington University School of Medicine

Saint Louis, Missouri, United States, 63110

United States, New Jersey

Rutgers Cancer Institute of New Jersey

New Brunswick, New Jersey, United States, 08901

United States, New York

Montefiore Medical Park

Bronx, New York, United States, 10461

Roswell Park

Buffalo, New York, United States, 14263

Icahn School of Medicine at Mount Sinai

New York, New York, United States, 10029

University of Rochester Medical Center

Rochester, New York, United States, 14642

United States, Ohio

University Hospitals Cleveland Medical Center

Cleveland, Ohio, United States, 44106

Ohio State University Comprehensive Cancer Center

Columbus, Ohio, United States, 43210

United States, Pennsylvania

University of Pennsylvania

Philadelphia, Pennsylvania, United States, 19104

Thomas Jefferson University Hospital, Sidney Kimmel Cancer Center

Philadelphia, Pennsylvania, United States, 19107

Fox Chase Cancer Center

Philadelphia, Pennsylvania, United States, 19111

United States, Virginia

University of Virginia Cancer Center

Charlottesville, Virginia, United States, 22908

VCU/Massey Cancer Center

Richmond, Virginia, United States, 23298

United States, West Virginia

West Virginia University

Morgantown, West Virginia, United States, 26506

Sponsors and Collaborators

Oncolytics Biotech

PrECOG, LLC.

More Information

• Responsible Party: Oncolytics Biotech
• ClinicalTrials.gov Identifier: NCT04215146
• Other Study ID Numbers: REO 028; PrE0113 ( Other Identifier: PrECOG, LLC. )
• First Posted: January 2, 2020
• Last Update Posted: September 2, 2022
• Last Verified: August 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Oncolytics Biotech:

Breast; Breast Cancer; Breast Cancer Metastatic; Locally Advanced Breast Cancer; Pelareorep; Avelumab; Paclitaxel; Reovirus; Oncolytic virus; HR+ breast cancer; HER2- breast cancer; Breast malignancy

Additional relevant MeSH terms:

Breast Neoplasms; Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Paclitaxel; Avelumab; Antineoplastic Agents, Phytogenic; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents, Immunological