Enhancing ICB Efficacy Through IL-1 Inhibition in TNBC

This study is a phase I/II open-label randomized clinical trial to examine whether administration of isunakinra (EBI-005), a modified recombinant IL1 receptor antagonist, can sensitize human TNBC to the PD1 inhibitor-pembrolizumab-based neoadjuvant chemotherapy (NAC/P) by changing the tumor microenvironment (TME) via reducing the recruitment of immunosuppressive tumorassociated macrophages (TAMs) and increasing activated cytotoxic T-lymphocytes (CTLs).

Inclusion Criteria: 1. Age \> 18 years 2. Newly diagnosed, locally advanced, previously untreated and centrally confirmed TNBC, as defined by the most recent American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines, and staging per current AJCC staging criteria for breast cancer as assessed by the investigator based on radiological and/or clinical assessment: Clinical stage T1c/N1-N2, T2-4/N0-2 3. Provides core needle biopsies consisting of at least 2 separate tumor cores from the primary tumor to the central laboratory 4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 5. Demonstrates adequate organ function 6. Participants of childbearing potential must be willing to use an adequate method of contraception for the course of the study Exclusion Criteria: 1. Male Gender 2. Luminal A/B and HER2 positive breast cancer 3. Multifocal early breast cancer 4. History of invasive malignancy ≤5 years prior to signing informed consent, except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer 5. Received prior chemotherapy, targeted therapy, and radiation therapy within the past 12 months 6. Has received prior therapy with an anti-PD1, anti-PDL1/-PDL2 agent or with an agent directed to another co-inhibitory T-cell receptor 7. Participated in an interventional clinical study with an investigational compound or device within 4 weeks of randomization for this study 8. Pre-existing inflammatory arthritis 9. Has received a live vaccine within 30 days of the first dose of study treatment 10. Has an active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs) 11. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy (i.e., dosing exceeding 10 mg daily of prednisone or equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment 12. Active or uncontrolled Human Immunodeficiency Virus (HIV), Hepatitis B or Hepatitis C 13. Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis 14. Has an active infection requiring systemic therapy 15. Has significant cardiovascular disease 16. Is pregnant or breastfeeding, or expecting to conceive children within the duration of the study 17. Has a known history of active tuberculosis (TB, Bacillus Tuberculosis) 18. Platelets ≤ 100x109/L. ANC ≤ 1.5 x109/L. Hemoglobin ≤ 80 g/L 19. ECOG≥2 20. History of stroke or intracranial hemorrhage within 6 months prior to enrollment 21. Presence of moderate or severe renal function impairment (estimated creatinine clearance \ 23 umol/L, serum albumin \< 35 g/L, INR \> 1.70) 23. Known hypersensitivity to E-coli derived proteins, isunakinra or any component of the product