Peripheral T Cell Determinants of Response and Resistance to Pembrolizumab in Melanoma
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 入组人数
- 25
- 试验地点
- 1
- 主要终点
- Number of Genes Predictive of Response at Baseline
研究概览
简要总结
This is a non-therapeutic study assessing peripheral T cell determinants of response and resistance to immunotherapy in patients with advanced melanoma.The hypothesis is that systemic T cells traffic into the tumor microenvironment (TME) can predict response and resistance to immunotherapy. These systemic tumor directed T cells can be defined by tumor/blood small conditional RNA (scRNA) using T cell receptor (TCR) as a barcode and can help predict response to Programmed death-1 (PD-1) therapy.
详细描述
Primary Objective:
To understand how the systemic immune profile (T cell activation and expansion in TME) changes in response to pembrolizumab therapy in patients with advanced melanoma on pembrolizumab monotherapy.
Exploratory Objectives :
I. To correlate the peripheral T cell profiles with the objective response rate (ORR) at 24 weeks in patients with advanced melanoma on pembrolizumab monotherapy.
II. To correlate the peripheral T cell profiles with progression free survival (PFS) in patients with advanced melanoma on pembrolizumab monotherapy.
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Prospective
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
- •Participants must have histologically confirmed locally advanced or metastatic melanoma and be starting on standard of care pembrolizumab monotherapy. Participants may have received any or no prior anti-cancer therapy without limitation.
- •Must have one or more sites of disease amenable to biopsy (tumor, skin, lymph node, pleural fluid, peritoneal fluid, cerebral spinal fluid (CSF)).
- •Have measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.
- •Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
- •Participants must be age 18 years or older on the day of signing informed consent.
- •Have the ability to provide written informed consent for the trial.
- •Be able and willing to comply with study procedures including provision of basic demographic information and medical history.
- •Be willing to receive periodic follow up phone calls to monitor health status and survival status.
排除标准
- •Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), OX 40, Cluster of Differentiation 137 (CD137)).
- •Has received prior systemic anti-cancer therapy including investigational agents within the prior 2 weeks.
- •Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug.
- •Has a contraindication to tissue biopsy for minimally invasive research-procedure.
- •Contraindication to phlebotomy (up to 40 milliliters (mL)) per phlebotomy every three weeks).
研究组 & 干预措施
Participants with Melanoma
Participants will undergo a pre-treatment tumor core biopsy and Peripheral blood mononuclear cell (PBMC) collection. Then, participants will be started on non-investigational pembrolizumab per standard of care and PBMCs will be collected every 3 weeks (1 cycle).
干预措施: Biopsy (Procedure)
Participants with Melanoma
Participants will undergo a pre-treatment tumor core biopsy and Peripheral blood mononuclear cell (PBMC) collection. Then, participants will be started on non-investigational pembrolizumab per standard of care and PBMCs will be collected every 3 weeks (1 cycle).
干预措施: Biospecimen Collection (Procedure)
结局指标
主要结局
Number of Genes Predictive of Response at Baseline
时间窗: At Baseline, 1 day
The investigators will identify the genes predictive of response to anti-programmed death-1(PD-1) therapy by testing for significant associations across expression rates of each gene and response/resistance, within a hurdle-Gaussian mixed-effect framework that accounts for variance across patients and technical noise present in single-cell data. The overall number of genes predictive of response at baseline will be reported.
Number of Genes Predictive of Response at 24 Weeks
时间窗: 24 weeks
The investigators will identify the genes predictive of response to anti-PD-1 therapy by testing for significant associations across expression rates of each gene and response/resistance, within a hurdle-Gaussian mixed-effect framework that accounts for variance across patients and technical noise present in single-cell data. The overall number of genes predictive of response at week 24 will be reported.
Number of T-cell Sub-populations
时间窗: Up to 24 weeks
The investigators will identify T cell sub-populations in the tumor-directed component in blood whose relative frequency is indicative of response to anti-PD-1 therapy, using a negative binomial regression model. The overall number of t-cell sub-populations will be reported.
Proportion of Participants With a Change in Clonal Expansion of T Cells Associated With Response to Anti-PD-1 Therapy
时间窗: Up to 24 weeks
The investigators will build a novel computational framework to identify T-cell clonal behavior associated with response to anti-PD-1 therapy using profiling of T-Cell Receptor (TCR) sequences at single-cell resolution to compare clonal expansion in each of the sub-population's association with response to anti-PD-1 therapy. The proportion of participants with a change in clonal expansion of T-cells associated with a response to anti-PD-1 therapy will be reported.
Proportion of Participants With a Change in Distribution of T Cells Associated With Response to Anti-PD-1 Therapy
时间窗: Up to 24 weeks
The investigators will build a novel computational framework to identify T-cell clonal behavior associated with response to anti-PD-1 therapy using profiling of TCR sequences at single-cell resolution to compare distribution of T cells in each of the sub-populations for their association with response to anti-PD-1 therapy. The proportion of participants with a change in distribution of T cells associated with response to anti-PD-1 therapy will be reported.
Number of Transcriptional Migration Events
时间窗: Up to 24 weeks
The investigators will search for "transcriptional migration" events, in which T cell clones change their transcriptional profile following treatment and will assess the predictive power of such events to the success of anti-PD-1 therapy. The overall number of transcriptional migration events will be reported.
次要结局
未报告次要终点