Rebooting Sensitivity to Checkpoint Blockade Therapy in Triple-Negative Breast Cancer With Isunakinra (RESETT- I)
试验速览
- 阶段
- 1 期
- 状态
- 尚未招募
- 入组人数
- 60
- 主要终点
- 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.
研究概览
简要总结
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).
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
- •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
研究组 & 干预措施
Group 1-Isunakinra treatment Group
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).
干预措施: Group 1-Isunakinra (Drug)
Group 2-Standard of care treatment group
Study participants randomized to Group 2, the control group, will receive standard pembrolizumab-based neoadjuvant chemotherapy (NAC/P).
结局指标
主要结局
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.
时间窗: 6 years
The following biomarkers will be evaluated, examining the changes in their expression level between baseline and after 8 weeks of NAC/P ± isunakinra: 1. TAMs 2. Lymphocyte subsets 3. Natural Killer cells 4. Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) 5. Inflammasome expression 6. Cytokines: IL-1β, IL-1α, IL-6, IL-8 and C-reactive protein (CRP)
次要结局
未报告次要终点