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

Recruiting

• Conditions: Melanoma; Advanced Melanoma
• Interventions: Procedure: Biopsy; Procedure: Biospecimen Collection

• Registration Number: NCT05105100
• Lead Sponsor: University of California, San Francisco

Brief Summary

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 PD-1 therapy.

Detailed Description

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.

Patients will be followed for 6 months from time of treatment initiation. After 6 months, patients do not need to be followed but standard of care scans and survival status can be assessed for up to 5 years.

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Study First Submitted: 2021-10-12
• Study First Submitted QC: 2021-10-25
• Study Start: 2021-10-29
• Study First Posted: 2021-11-03
• Status Verified: 2024-12
• Last Update Submitted: 2024-12-03
• Last Update Posted: 2024-12-05
• Primary Completion: 2026-08-28
• Study Completion: 2026-08-28

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 25

Inclusion Criteria

1. Patients must have histologically confirmed locally advanced or metastatic melanoma and be starting on standard of care pembrolizumab monotherapy. Patients may have received any or no prior anti-cancer therapy without limitation.
2. Must have one or more sites of disease amenable to biopsy (tumor, skin, lymph node, pleural fluid, peritoneal fluid, cerebral spinal fluid (CSF)).
3. 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.
4. Participants must be age 18 years or older on the day of signing informed consent.
5. Have the ability to provide written informed consent for the trial.
6. Be able and willing to comply with study procedures including provision of basic demographic information and medical history.
7. Be willing to receive periodic follow up phone calls to monitor health status and survival status.

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Exclusion Criteria

1. 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)).
2. Has received prior systemic anti-cancer therapy including investigational agents within the prior 2 weeks.
3. 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.
4. Has a contraindication to tissue biopsy for minimally-invasive research-procedure
5. Contraindication to phlebotomy (up to 20 milliliters (mL)) per phlebotomy every three weeks).

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Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
Participants with Melanoma	Biopsy	Participants will undergo a pre-treatment tumor core biopsy and Peripheral blood mononuclear cell (PBMC) collection. Then, patients will be started on pembrolizumab per standard of care and PBMCs will be collected every 3 weeks (1 cycle)
Participants with Melanoma	Biospecimen Collection	Participants will undergo a pre-treatment tumor core biopsy and Peripheral blood mononuclear cell (PBMC) collection. Then, patients will be started on pembrolizumab per standard of care and PBMCs will be collected every 3 weeks (1 cycle)

Primary Outcome Measures

Name	Time	Method
Number of genes predictive of response at 24 weeks	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	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	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	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	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	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.

Trial Locations

Locations (1)

University of California, San Francisco; 🇺🇸 San Francisco, California, United States