Enhancing ICB Efficacy Through IL-1 Inhibition in TNBC

Official title

Rebooting Sensitivity to Checkpoint Blockade Therapy in Triple-Negative Breast Cancer With Isunakinra (RESETT- I)

Overview

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).

Detailed description

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.

Interventions

• Drug Group 1-Isunakinra
  isunakinra at a dose of 50mg SC daily x 24 weeks in addition to standard pembrolizumab-based neoadjuvant chemotherapy (NAC/P).

Primary outcome measures

• Outcome-Study will test whether IL1 blockade can reduce TAM and sensitize human TNBCs to ICB. Outcome measure-changes in the TME induced by the addition of isunakinra to NAC/P will be determined. [Time frame: 6 years]

Eligibility criteria

Inclusion criteria

• Age > 18 years
• 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

• Provides core needle biopsies consisting of at least 2 separate tumor cores from the primary tumor to the central laboratory
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Demonstrates adequate organ function
• Participants of childbearing potential must be willing to use an adequate method of contraception for the course of the study

Exclusion criteria

• Male Gender
• Luminal A/B and HER2 positive breast cancer
• Multifocal early breast cancer
• 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
• Received prior chemotherapy, targeted therapy, and radiation therapy within the past 12 months
• Has received prior therapy with an anti-PD1, anti-PDL1/-PDL2 agent or with an agent directed to another co-inhibitory T-cell receptor
• Participated in an interventional clinical study with an investigational compound or device within 4 weeks of randomization for this study
• Pre-existing inflammatory arthritis
• Has received a live vaccine within 30 days of the first dose of study treatment
• 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)
• 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
• Active or uncontrolled Human Immunodeficiency Virus (HIV), Hepatitis B or Hepatitis C
• Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis
• Has an active infection requiring systemic therapy
• Has significant cardiovascular disease
• Is pregnant or breastfeeding, or expecting to conceive children within the duration of the study
• Has a known history of active tuberculosis (TB, Bacillus Tuberculosis)
• Platelets ≤ 100x109/L. ANC ≤ 1.5 x109/L. Hemoglobin ≤ 80 g/L
• ECOG≥2
• History of stroke or intracranial hemorrhage within 6 months prior to enrollment
• Presence of moderate or severe renal function impairment (estimated creatinine clearance <60 mL/min/1.73m2)
• 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)
• Known hypersensitivity to E-coli derived proteins, isunakinra or any component of the product

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Center list to be confirmed — check the primary protocol.

Identifiers

NCT: NCT07698106 · RESETT-I

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗