Advanced Melanoma, Melanoma
Conditions
Keywords
Peripheral T Cell, Pembrolizumab
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 Programmed death-1 (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. 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.
Interventions
PROCEDUREBiopsy
Tumor tissue collection
PROCEDUREBiospecimen Collection
Intravenously Blood draw
Sponsors
University of California, San Francisco
Merck Sharp & Dohme LLC
Study design
Observational model
COHORT
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. 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. 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.
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 40 milliliters (mL)) per phlebotomy every three weeks).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Genes Predictive of Response at Baseline | 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 | 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 | 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 | 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 | 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 | 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. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORAdil Daud, MD
University of California, San Francisco
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Customized 30-39 years old | 1 Participants |
| Age, Customized 40-49 years old | 2 Participants |
| Age, Customized 50-59 years old | 5 Participants |
| Age, Customized 60-69 years old | 1 Participants |
| Age, Customized 70-79 years old | 10 Participants |
| Age, Customized 80-89 years old | 6 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 24 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race (NIH/OMB) White | 22 Participants |
| Region of Enrollment United States | 25 participants |
| Sex: Female, Male Female | 9 Participants |
| Sex: Female, Male Male | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 25 |
| other Total, other adverse events | 15 / 25 |
| serious Total, serious adverse events | 1 / 25 |
Outcome results
None listed