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Completed

NCT Number: NCT05105100

Peripheral T Cell Determinants of Response and Resistance to Pembrolizumab in Melanoma

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.

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Key information

Conditions

Melanoma Advanced Melanoma Neoplasms Neoplasms by Histologic Type Neoplasms by Site Neoplasms, Germ Cell and Embryonal Neoplasms, Nerve Tissue Neuroectodermal Tumors Neuroendocrine Tumors Nevi and Melanomas Skin Diseases Skin Neoplasms Skin and Connective Tissue Diseases

Age range

18 year and older

Sex eligibility

All sexes

Study type

Observational

Primary location

University of California, San Francisco

San Francisco, California, 94143, United States

About this study

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.

III. To correlate the peripheral T cell profiles with overall survival (OS) in patients with advanced melanoma on pembrolizumab monotherapy.

IV. To correlate the peripheral T cell profiles with toxicity profile.

V. Transcriptional and phenotypic features of tumor directed T cells in blood using a combination of phenotypic markers derived from COMET and cite-seq.

Outline:

Participants will have blood drawn and tumor biopsied. Participants will be followed for 6 months from time of treatment initiation. After 6 months, participants do not need to be followed but standard of care scans and survival status can be assessed for up to 5 years.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • 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 1.1. 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.

Exclusion criteria

  • 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).

Treatment and study plan

Biopsy

Procedure

Tumor tissue collection

Other names: Excisional Biopsy

Biospecimen Collection

Procedure

Intravenously Blood draw

Other names: Specimen Collection

Primary outcomes

  1. Number of Genes Predictive of Response at Baseline

    Time frame: 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.

  2. Number of Genes Predictive of Response at 24 Weeks

    Time frame: 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.

  3. Number of T-cell Sub-populations

    Time frame: 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.

  4. Proportion of Participants With a Change in Clonal Expansion of T Cells Associated With Response to Anti-PD-1 Therapy

    Time frame: 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.

  5. Proportion of Participants With a Change in Distribution of T Cells Associated With Response to Anti-PD-1 Therapy

    Time frame: 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.

  6. Number of Transcriptional Migration Events

    Time frame: 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.

Sponsors and collaborators

Lead sponsor

University of California, San Francisco

Other

Collaborators

  • Merck Sharp & Dohme LLC

Registry information

Important dates

Study start
2021
Primary completion
2025
Study completion
2025
First posted
Nov 3, 2021
Registry last updated
Apr 6, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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