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.
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.
Number of T-cell sub-populations
时间窗: Baseline and 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. We will test for predictive differences in relative frequencies before and after treatment initiation separately, as well as when combining both time points with appropriate interaction terms
Number of genes predictive of response at Baseline
时间窗: Baseline
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.
Proportion of participants with a change in clonal expansion of T cells associated with response to anti-PD-1 therapy
时间窗: 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 clonal expansion in each of the sub-populations for their association with response to anti-PD-1 therapy.
Proportion of participants with a change in distribution of T cells associated with response to anti-PD-1 therapy
时间窗: 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.
Number of transcriptional migration events
时间窗: 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.
次要结局
未报告次要终点