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).

Pre-clinical work has found that tumor cell IL-1β drives TAM recruitment, immunosuppression, and tumor progression in TNBC. In fact, experimental evidence, across most cancer types, supports a tumor-promoting role for IL-1β making IL-1β a target with clear therapeutic potential. Roles for IL-1β in growth, invasion and angiogenesis, metastases, stemness and epithelial-mesenchymal transition (EMT) and tumoral recruitment of TAMs and other pro-tumoral inflammatory cells have been extensively described, and IL-1β upregulation is generally associated with poorer prognosis. The best available clinical information suggests that targeting IL-1β reduces cachexia and remarkably is associated with a greater than 50% reduction of death from all cancers (phase 3 Cantos trial, testing the IL-1β inhibitor canakinumab (Ilaris®) to treat heart failure in a cohort of 10,061 patients). We are the first to suggest that TNBCs are the "perfect storm" for IL-1β production, with Notch providing IL-1β priming and the inflammasome ensuring cleavage, making TNBC an ideal candidate for IL-1β blockade. Supporting this, our most recent pre-clinical work shows that IL1β antagonists can synergize with ICB to eliminate TNBC.

This study is a phase I/II open-label randomized clinical trial evaluating the immunologic effects within the tumor, microenvironment, and host blood of patients treated with either: Group 1 Study participants randomized to Group 1 treatment group will receive isunakinra at a dose of 50mg SC daily x 24 weeks in addition to standard pembrolizumab-based neoadjuvant chemotherapy (NAC/P). Group 2 Study participants randomized to Group 2, the control group, will receive standard pembrolizumab-based neoadjuvant chemotherapy (NAC/P).

A total of 60 patients will be recruited across 3 institutions, randomized 1:1 to treatment (n=30) versus control (n=30).

The proposed study may provide important data regarding the mechanism of action, safety, feasibility and efficacy of isunakinra when added to NAC/P. It will inform sample size for a definitive phase 3 study designed to prove that isunakinra improves patient outcome.

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 <60 mL/min/1.73m2)
22. Patients with mild, moderate, or severe hepatic impairment or inadequate liver function (total bilirubin > 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

Female