neoBREASTIM: Atezolizumab Plus RP1 Oncolytic Immunotherapy in the NeoAdjuvant Setting of Triple-Negative Breast Cancer

Study Overview
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Brief Summary
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Neoadjuvant treatment is an important part of the treatment strategy for locally advanced TNBC having established a positive and significant correlation of pathologic Complete Response (pCR) with long-term clinical benefit such as Event-Free Survival (EFS) and Overall Survival (OS) as shown via large meta-analysis. Much effort has been made to identify novel agents and new drug combinations that can improve pCR rates in this specific clinical setting, which is the leading rationale to evaluate RP1 oncolytic immunotherapy in combination with Atezolizumab.

Detailed Description
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The combination of RP1 plus Atezolizumab, while being expected to result in increased efficacy, is not expected to result in significant additional toxicity, as compared to either agent alone. Capitalizing on the strong prognostic and predictive value of the TIL infiltrate in early-stage TNBC and the capacity of circulating tumor DeoxyriboNucleic Acid (ctDNA) detection to predict response to immunotherapy and NeoAdjuvant Chemotherapy (NAC), neoBREASTIM - a single-arm phase 2 study - will evaluate a novel, biomarker-driven combination of Atezolizumab plus RP1 oncolytic immunotherapy in the neo-adjuvant setting of patients diagnosed with early-stage, TIL-high TNBC.

Official Title
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neoBREASTIM: A Phase 2 Study of Atezolizumab Plus RP1 Oncolytic Immunotherapy in the NeoAdjuvant Setting of Triple-Negative Breast Cancer (TNBC)

Conditions
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Triple Negative Breast Neoplasms

Intervention / Treatment
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* Combination Product: Atezolizumab + RP1


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female subject Age ≥ 18 years old. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ≤ 1. Newly diagnosed Triple-Negative Breast Cancer (TNBC), defined as the absence of estrogen expression and progesterone expression, and of Human Epidermal growth factor Receptor 2 (HER2) overexpression, must be determined by local testing of a screening tumor sample as defined by American Society of Clinical Oncology/College of American Pathologists guidelines. TNBC defined as the following combined primary tumor (T), regional lymph node (N), and metastatic (M) American Joint Committee on Cancer staging criteria: cT ≥15 - ≤30 mm, N0, M0 according to Mammogram, breast Ultrasound and MRI, and PET-CT. In case of a difference in the measurement of the primary tumor among different imaging methods, the breast MRI measurement is the reference. Unicentric, unifocal and unilateral disease. Tumor-infiltrating lymphocytes (TILs) ≥ 30%, as defined by the International TILs Working Group 2014. ctDNA dosing at baseline. Agreement to provide tissue samples (tumor biopsy at screening and on-treatment), and at surgery for immune monitoring and translational research activities. Agreement to perform blood samples at screening, on-treatment, and at surgery for immune monitoring and translational research activities. Exclusion Criteria: Inflammatory breast cancer. Prior treatment with an oncolytic virus-based therapy. Patients with active significant herpetic infections or prior complications of Herpes Simplex Virus-1 (HSV-1) infection. Patients who require intermittent or chronic use of systemic (oral or IV) antivirals with known antiherpetic activity (e.g., acyclovir). Diagnosis of immunodeficiency. Has active autoimmune disease (e.g. inflammatory bowel disease, systemic lupus erythematosus, ankylosing spondylitis, scleroderma, and multiple sclerosis, celiac disease, Wegener's granulomatosis) that has required systemic treatment in the past 3 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Prior systemic immunosuppressive medication (except physiologic corticosteroid replacement therapy) within 30 days of planned start of study therapy. Any live (attenuated) vaccine within 14 days of planned start of study therapy. Prior immunotherapy, including tumor vaccine, cytokine, anti-CTLA4, PD-1/PD-L1 blockade or similar agents, T cell receptor-based (TCR-based) or Chimeric Antigen Receptor-T (CAR-T) cell based adoptive cell therapy. Known history of, or any evidence of active, non-infectious pneumonitis.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: An open-label, monocentric, single arm, phase II study with a safety run-in.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Atezolizumab plus RP1 (Immulytic™) oncolytic immunotherapy<br>Atezolizumab IV q2w RP1 (Immulytic™) by imaging-guided intra-tumor (IT) route. | Combination Product: Atezolizumab + RP1<br>* Patients will be treated in a window period (ie 3 treatment cycles). After evaluation, patients that had no increase in ctDNA after 3 cycles (see Definition of ctDNA status) will continue on the same treatment (intratumoral injections of RP1 in combination with Atezolizumab) for a total of 10 treatment cycles prior to surgery.<br>* Other names: Vusolimogene Oderparepvec;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety of the combination Atezolizumab plus RP1 oncolytic during the safety run-in phase | Incidence of combination Atezolizumab plus RP1 adverse events (AEs) graded according to NCI CTCAE v5.0 and nature and severity | 9 months | 
| Toxicity of the combination Atezolizumab plus RP1 oncolytic immunotherapy during the safety run-in phase. | Dose Limiting Toxicity (DLT) during the first cycle of treatment of the combination Atezolizumab plus RP1 oncolytic immunotherapy | 9 months | 
| Residual Cancer Burden (RCB) 0-1 during the phase II part | Rate of RCB 0-1 at time of surgery (in patients with no increase in ctDNA after cycle 3) | 30 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response rate of RCB Score <= 1 at three cycles | Rate of RCB 0-1 after cycle 3 (in patients with no increase in ctDNA after cycle 3) | 26 months | 
| Safety and toxicity of the combination Atezolizumab plus RP1 oncolytic immunotherapy | Incidence, nature and severity of adverse events (AEs) graded according to NCI CTCAE v5.0 from the treatment start to the surgery | 60 months | 
| Invasive disease-free survival (iDFS) | iDFS will be measured using regular follow-up visits | 60 months | 
| Percentage of TILs | The percentage of TILs will be estimated and compared between RCB rates 0-1 versus 2-3 | 30 months | 
| Pre-treatment expression of Programmed Death-Ligand 1 (PD-L1) | Expression of PD-L1 will be estimated and compared between RCB rates 0-1 versus 2-3 | 30 months | 
| Correlation between RCB rates and response by Positron Emission Tomography-Scan (PET-CT) or breast MRI | To correlate the response by RCB rates with response by PET-CT or breast MRI will be studied | 60 months | 
| RCB rates and response | To correlate the response by breast MRI with RCB 0-1 rates, | 60 months | 
| Breast Conservation Surgery (BCS) | The rate of Breast Conservation Surgery (BCS) will be presented | 30 months | 
| Correlation between RCB rates and radiomics analyses | To correlate the RCB rates with response by radiomics analyses. | 30 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Triple Negative Breast Cancer, Early-stage, Immunotherapy, Oncolytic virus